Polyunsaturated bicyclic compounds, their preparation and use of same as starting materials for preparing monounsaturated bicyclic compounds

ABSTRACT

New polyunsaturated compounds, their preparation and their use as starting materials for preparing monounsaturated bicyclic compounds useful as intermediates in the preparation of macrocyclic ketones.

SUMMARY OF THE INVENTION

The invention relates to compounds of formula ##STR1## wherein symbol Rrepresents a hydrogen atom or a methyl radical.

The invention also relates to a process for preparing said compounds(III), which comprises treating with a strong base a compound of formula##STR2## wherein symbol R is defined in formula (III) and Q representsan alkyl or an aryl radical.

The invention further relates to the use of said compounds (III) asstarting materials for preparing compounds of formula ##STR3## whereinsymbol R is defined hereinabove, which comprises hydrogenating saidcompound (III) in the presence of a metal catalyst.

The invention finally relates to compounds of formula ##STR4## whereinsymbol R represents a hydrogen atom or a methyl radical and Q representsan alkyl or an aryl radical.

BACKGROUND OF THE INVENTION

EXALTONE® and muscone, two macrocyclic ketones, are very appreciated inthe art of perfumery for their elegant and tenacious musky odour. Bothcompounds have been known for several decades and since their discoverya variety of syntheses have been proposed and described in thescientific literature [see e.g.: J. Chem. Soc. 1964, 4154; Tetrahedron20, 2601 (1964); Helv. Chim. Acta 50, 705 (1967) and Helv. Chim. Acta50, 708 (1967)]. So far, however, most of the published methods couldnot be successfully applied to their industrial scale preparation,especially in view of their complexity or in view of the low yieldsachieved in the critical reaction steps.

One of the prior known syntheses [Helv. Chim. Acta 50, 705 (1967)] makesuse of the compound of formula ##STR5## (R=H, in formula I) asintermediate in the synthesis of EXALTONE® (cyclopentadecanone), and ofthe corresponding methyl derivative of formula ##STR6## (R=methyl, informula I) in the synthesis of muscone. Both intermediate compounds canbe obtained from cyclododecanone by a condensation reaction and asubsequent cyclization, hydrogenation and dehydration. Due to the ratherpoor overall yields achieved, such synthetic routes have not beendeveloped industrially.

The advantage of the invention consists in providing a new and originalsynthetic process for preparing the above mentioned intermediatecompounds of formula (I), thus making the preparation of the desiredmacrocycles more convenient and industrially feasible.

PREFERRED EMBODIMENTS OF THE INVENTION

In formula (II) give above, symbol Q represents preferably a lower alkylradical such as for instance a methyl, ethyl, propyl or butyl radical,or an aryl radical such as phenyl or p-tolyl.

According to the invention, compounds (II) are treated with a strongbase, in the presence or absence of an organic solvent or mixture oforganic solvents, to afford corresponding polyunsaturated bicycliccompounds (III). Formally, the reaction consists in an initialcondensation reaction followed by an elimination, both steps beingeffected in the presence of the strong base. Condensation and subsequentelimination of water yield to an intermediate compound having formula##STR7## (R and Q are defined as above) which can be, if necessary,isolated from the reaction mixture. Said intermediate compound (IV) canbe further treated with a strong base to afford, after a secondelimination reaction, the desired compound (III). For practical andeconomical reasons however, condensation and both eliminations areeffected in one single reaction step.

As strong base, one can advantageously use a strong organic base such asan alkali metal alkoxide, potassium tert-butoxide, sodium methoxide ortert-pentoxide for example, or even potassium or sodium hydride oramide. In certain cases, mixtures of organic bases, sodium methoxide andpotassium tert-pentoxide e.g., can be used. A strong mineral base suchas potassium hydroxyde can also be used in accordance with the processof the invention.

The said base is used in excess with respect to compound (II), generallyin the proportions of at least 2 to 2.5 equivalents of the base for 1equivalent of compound (II). Depending on the nature of the base, onecan also use 6 or even 10 equivalents of the base for 1 equivalent ofcompound (II).

As mentioned hereinabove, the treatment of compound (II) can be effectedin the absence of any solvent, said compound (II) being merely heated inthe presence of the selected base. For example,2-(2-methyl-3-phenylsulfonyl-prop-1-yl)-cyclododecanone can easily beconverted into the corresponding compound (III) by heating at about 160°C., in the presence of potassium tert-butoxide.

When the above treatment is effected in the presence of an organicsolvent or a mixture of organic solvents, one can advantageously use anaromatic hydrocarbon, toluene or xylene e.g., an aliphatic alcohol, anether such as tetrahydrofurane, dioxane or dimethoxy-ethane e.g., oreven dimethyl-sulfoxide, ethylene-diamine orhexamethyl-phosphorous-triamide (HMPT). Depending on the nature of thesolvent or mixture of solvents which is used, the reaction temperaturemay vary within about 60° and 160° C., preferably within about 100° and120° C. More generally, the said temperature is of the order of theboiling temperature of the solvent or mixture of solvents used.

The polyunsaturated bicyclic compound (III) thus obtained can be thenconverted into the corresponding monounsaturated derivative (I), by ahydrogenation in the presence of a metal catalyst. The saidhydrogenation is generally effected at atmospheric pressure, in thepresence of a catalyst which is able to produce simultaneously theisomerization of an ethylenic double bond: palladium on charcoal ispreferably used.

The said hydrogenation can be effected in the presence of an inertorganic solvent, e.g. an aliphatic hydrocarbon, petrol ether or anaromatic hydrocarbon, benzene, toluene or xylene, e.g., or an alcohol oran ether; in fact, one can use any solvent or mixture of solvents whichis able to dissolve compound (III). The hydrogenation is moreovereffected at a temperature generally comprised between about 20° and 120°C., preferably between about 75° and 115° C.

Compounds (II) used as starting materials in the process of theinvention are novel compounds. They can be easily prepared from2-allyl-cyclododecanone or 2-methallyl-cyclododecanone, respectively,after radical initiated addition of the appropriate thiol and subsequentoxidation. Each of the above reaction steps can be carried out inaccordance with the techniques known in the art: a detailed descriptionthereof is given in the examples. The said preparation can also beillustrated as follows: ##STR8##

In the above reaction scheme, symbols R and Q are defined as mentionedpreviously.

The followings examples are deemed to illustrate the invention in a moredetailed manner (temperatures in degrees centigrade).

EXAMPLE 1 Bicyclo[10.3.0]pentadeca-1,12-diene(intermediate compound notisolated)

(a) method with potassium tert-butoxide

0.728 g (2 mmole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone and0.560 g (5 mmole) of potassium tert-butoxide in 8 ml of toluene wereheated to reflux for 1 hour in a reaction vessel fitted with a waterseparator. After cooling to 10°, addition of water (15 ml), extractionwith ether (2×15 ml), washing of the organic layer with brine (15 ml),then with water, drying over Na₂ SO₄, evaporation and final distillation(0.02 Torr--bath temperature: 140°) there were isolated 0.340 g (83%yield) of the desired compound.

IR: 2910, 1460, 1440, 925, 915, 845 cm⁻¹ ;

NMR (90 MHz): 1.02-1.76 (14H, m); 1.95-2.68 (8H, m); 5.47 (1H, t, J=7.5Hz);5.72 (1H, broad s) δ ppm;

MS: M⁺ +1=205 (15), M⁺ =204 (84); m/e=175 (8), 161 (34), 148 (60), 147(78), 134 (42), 133 (100), 119 (62), 106 (42), 105 (57), 93 (47), 91(81), 79 (70), 67 (58).

(b) method with potassium tert-butoxide/sodium methoxide

29.0 ml of a 30% solution of sodium methoxide in methyl alcohol (0.15mole) were added dropwise to a mixture of 36.4 g (0.10 mole) of2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone and 200 ml of toluene,kept at reflux in a reaction vessel fitted with a water separator(addition period: ca. 1 hour). After this first addition, 14.6 g (0.13mole) of potassium tert-butoxide were added to the reaction mixture,which was then heated to reflux during 4 hours. After the usualtreatments of extraction and distillation, there were isolated 17.1 g(84% yield) of the desired compound.

(c) method with sodium methoxide

2.37 ml of a 30% solution of sodium methoxide in methyl alcohol (10.2mmole) were added dropwise to a solution of 0.728 g (2.0 mmole) of2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone in 10 ml of toluene asindicated sub letter b). After 90 min. of heating, 0.57 ml (8.0 mmole)of dimethylsulfoxide (DMSO) were added to the reaction mixture which wasthen heated to reflux for 4 further hours. After extraction anddistillation, there were isolated 0.310 g (76% yield) of the desiredcompound.

(d) method with potassium hydroxide

10.92 g (0.03 mole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanoneand 11.0 g (0.197 mole) of freshly powdered KOH in 40 ml of toluene wereheated to reflux for 30 min. as indicated sub letter (b). After additionof 6 ml (0.085 mole) of DMSO, the reaction mixture was heated to refluxfor 12 further hours, then cooled, extracted and finally distilled asindicated hereinabove to afford 5.32 g (87% yield) of the desiredcompound.

By adding 13.5 g (0.24 mole) of powdered KOH instead of the abovementioned 11 g, the heating period in the presence of DMSO could bereduced to 30 min.

(e) method with potassium hydroxide/ethyl alcohol

0.728 g (2 mmole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone and0.730 g (13 mmole) of KOH in solution in 10 ml of ethyl alcohol wereheated to reflux for 1 hour. After addition of 2 ml of DMSO, thereaction mixture was heated to 120° and the excess of ethyl alcoholdistilled therefrom. The resulting mixture was then heated at 110° for12 hours, then treated as indicated hereinabove to afford 0.29 g (71%yield) of the desired compound.

(f) method with sodium hydride

0.144 g (6 mmole) of NaH and 10 ml of DMSO were first heated at 80° for30 min. Once the hydrogen evolution was terminated, 0.728 g (2 mmole) of2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone were added to the abovemixture and the resulting reaction mixture further heated at 100° for 4hours. After the treatments of extraction and distillation mentionedhereinabove, there were isolated 0.326 g (80% yield) of the desiredcompound.

(g) method with sodium hydride/ethylene-diamine

0.720 g (2 mmole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone,0.144 g (6 mmole) of sodium hydride and 10 ml of ethylene-diamine wereheated at 100° for 4 hours, then cooled, extracted and finally distilledas indicated hereinabove to afford the desired compound in a 75% yield.

(h) method with sodium tert-pentoxide

18.2 g (0.05 mole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone,33.0 g (0.30 mole) of sodium tert-pentoxide and 100 ml of toluene weresubjected to the treatments described sub letter (a). After addition of15 ml of DMSO, heating at 110° for 4 hours and final treatments asindicated hereinabove, there were isolated 7.75 g (76% yield) of thedesired compound.

EXAMPLE 2 Bicyclo[10.3.0]pentadeca-1,12-diene (intermediate compoundisolated)

(i) 0.728 g (2.0 mmole) of2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone and 0.336 g (3.0 mmole)of potassium tert-pentoxide in 8 ml of toluene were heated during 30min. at 50°. After cooling, addition of water (15 ml), extraction withether (2×15 ml), washing and drying as indicated hereinabove andevaporation, there were isolated 0.673 g of crude material. Aftercrystallization in a diethyl ether/petrol ether mixture there werefinally obtained 0.598 g (86% yield) of a pure compound having thefollowing structural formula ##STR9## The above compound wascharacterized as follows:

m.p. 94°-99°

IR: 2920, 1460, 1440, 1300, 1285, 1125, 1080 cm⁻¹ ;

NMR (90 MHZ): 0.95-1.95 (18H, m); 2.00-2.70 (6H, m); 4.20 (1H, d, J=7Hz); 7.40-7.95 (5H, m) δ ppm;

MS: m/e=219 (15), 218 (8), 147 (7), 133 (7), 119 (14), 107 (17), 105(15), 95 (35), 91 (24), 81 (21), 77 (19), 55 (19), 44 (30), 40 (100).

Analogous results were achieved by replacing in the above examplepotassium tert-butoxide by an equivalent amount of sodium methoxide, orby making use of 7 equivalents of powdered potassium hydroxide for 1equivalent of starting 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone(88% yield).

(ii) The thus prepared compound was then converted into the desiredtitle compound by heating at 110° during 1 hour, in the presence of 1equivalent of potassium tert-butoxide (82% yield).

2-(3-Phenylsulfonyl-prop-1-yl)-cyclododecanone used hereinabove(Examples 1 and 2) as starting material was prepared as follows: 222 g(1 mole) of 2-allyl-cyclododecanone--Helv. 54, 2889 (1971)--in admixturewith 132 g (1.2 mole) of thiophenol and 3.0 g ofα,α'-azoisobutyronitrile were heated at 100° for 10 hours, an additionalamount of 6.0 g of α,α'-azoisobutyronitrile being added over thisperiod, portionwise, to the reaction mixture. After dilution with anexcess amount of trichloroethane and cooling in an ice-bath, 376 ml (2.6mole) of 40% peracetic acid were progressively added to the reactionmixture, under good stirring (reaction temperature: 25°-30°). Aftertreatment with an excess amount of an aqueous solution of NaHSO₃(elimination of peroxides), a 10% solution of NaOH in water was addedthereto until pH 8-9 (temperature ca. 10°). After extraction withmethylene chloride (2×300 ml), successive washings and water and brine,drying over Na₂ SO₄, evaporation and crystallization of the cruderesidue in a CH₂ Cl₂ /diethyl ether/petrol ether mixture, there werefinally isolated 332 g (91% yield) of the desired compound, m.p.97°-102°.

IR: 2950, 1700, 1465, 1445, 1300, 1145, 1080, 790 cm⁻¹ ;

NMR (60 MHz): 1.00-2.00 (22H, m); 2.30-2.75 (3H, m); 2.90-3.25 (2H, m);7.50-8.02 (5H, m) δ ppm;

MS: M⁺ =364 (30); m/e=254 (8), 240 (15), 223 (12), 143 (32), 98 (41), 55(100), 41 (59).

EXAMPLE 3 14-Methyl-bicyclo[10.3.0]pentadeca-1,12-diene (intermediatecompound not isolated)

11.35 g (0.03 mole) of2-(2-methyl-3-phenylsulfonyl-prop-1-yl)-cyclododecanone and 11.0 g(0.197 mole) of powdered KOH in 30 ml of toluene were first heated toreflux during 30 min., in a reaction vessel fitted with a waterseparator. After addition of 6 ml of DMSO, the reaction mixture wasfurther heated at 110°, for 12 hours. After the treatments ofextraction, washing, drying and distillation (0.05 Torr--bathtemperature: 150°) described in Example 1, there were isolated 5.61 g(86% yield) of the desired compound.

IR: 2920, 1460, 1440, 835 cm⁻¹ ;

NMR (90 MHz): 1.00 (3H, d, J=7 Hz); 1.08-1.73 (14H, m); 1.80-2.40 (5H,m);2.55-2.91 (2H, m); 5.40 (1H, t, J=7.5 Hz); 5.60 (1H, broad s) δ ppm;

MS: M⁺ =218 (93); m/e=203 (80), 175 (30), 161 (70), 147 (100), 133 (92),112 (68), 107 (60), 106 (44), 105 (68), 94 (55), 93 (72), 91 (75), 79(55), 67 (32), 55 (38).

EXAMPLE 4 14-Methyl-bicyclo[10.3.0]pentadec-1,12-diene (intermediatecompound isolated)

(i) 0.58 ml of a 30% solution of sodium methoxide in methyl alcohol (3mmole) were added to 0.756 g (2 mmole) of2-(2-methyl-3-phenylsulfonyl-prop-1-yl)-cyclododecanone in 8 ml oftoluene and the resulting mixture was heated to reflux for 1 hour asindicated in Example 3. After the above treatments of extraction anddistillation (0.01 Torr--bath temperature: 200°), there were isolated0.627 g (87% yield) of a compound having the formula ##STR10## The abovecompound was characterized as follows:

IR: 2945, 1470, 1445, 1300, 1140, 1080 cm⁻¹ ;

NMR (90 MHz): 0.90-1.80 (22H, m); 2.20-3.00 (4H, m); 3.78 (1H, broad s);7.35-7.96 (5H, m) δ ppm;

MS: m/e=220 (9), 219 (48), 149 (9), 147 (12), 133 (13), 123 (13), 119(24), 109 (22), 107 (33), 105 (28), 95 (38), 94 (71), 93 (30), 91 (45),81 (62), 79 (29), 69 (44), 67 (31), 57 (36), 55 (50), 44 (44), 43 (40),41 (56), 40 (100).

(ii) The thus prepared compound was then converted into the desiredtitle compound by heating at 110° in toluene, in the presence of 1equivalent of potassium tert-butoxide and by subsequent treating thereaction mixture as described in Example 3.

2-(2-Methyl-3-phenylsulfonyl-prop-1-yl)-cyclododecanone used hereinabove(Examples 3 and 4) as starting material was prepared as follows: 235 g(1 mole) of 2-methallyl-cyclododecanone--Chem. Comm. 1976, 1021--inadmixture with 132 g (1.2 mole) of thiophenol and 3.0 g (0.018 mole) ofα,α'-azoisobutyronitrile were heated at 115° for 32 hours andsubsequently subjected to oxidation in accordance with the methoddescribed in Example 2 for2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone to afford, after theabove mentioned treatments of extraction and purification, 325 g (86%yield) of the desired compound, m.p. 98°-103°.

IR: 2950, 1705, 1470, 1450, 1305, 1145, 1085 cm⁻¹ ;

NMR (60 MHz): 0.90-2.20 (24H, m); 2.30-2.75 (3H, m); 3.00 (2H, d, J=5Hz); 7.50-8.02 (5H, m) δ ppm;

MS: M⁺ =378 (14); m/e=255 (20), 237 (22), 143 (15), 98 (24), 95 (32), 83(52), 81 (49), 77 (50), 69 (36), 67 (32), 55 (100), 43 (41), 41 (83).

EXAMPLE 5 Bicyclo[10.3.0]pentadec-1(12)-ene

6.06 g of bicyclo[10.3.0]pentadec-1,12-diene--crude material; seeExample 1--in 40 ml of toluene were hydrogenated at 100°, underatmospheric pressure, in the presence of 0.6 g of 10% palladium oncharcoal. After 60 min. of hydrogenation, the reaction mixture wascooled, filtered on CELITE and finally distilled (0.02 Torr--bathtemperature: 140°) to afford 5.2 g (84% yield) of the desired titlecompound having a purity of 93% according to vapour phase chromatographyanalysis (CARBOWAX 10%--1.6 m--140°). The compound thus prepared wasfound identical with a sample prepared according to J. Amer. Chem. Soc.79, 5558 (1957).

Analogous results were obtained by subjecting the starting material tohydrogenation at 115° in xylene or at 75° in ethyl alcohol.

EXAMPLE 6 14-Methyl-bicyclo[10.3.0]pentadec-1(12)-ene

6.48 g of 14-methyl-bicyclo[10.3.0]pentadeca-1,12-diene--crude material;see Example 3--in 40 ml of toluene were hydrogenated in the presence of0.65 g of 10% palladium on charcoal as indicated in Example 5. After theabove treatments of filtration and distillation, there were obtained5.69 g (86% yield) of the desired title compound having a purity of 95%according to the vapour phase chromatography analysis (CARBOWAX 10%--1.6m--140°). The compound thus prepared was found identical with a sampleprepared according to Chem. Abstr. 70, 88108 v (1970).

EXAMPLE 7 14-Methyl-bicyclo[10.3.0]pentadeca-1,12-diene

0.756 g (2 mmole) of2-(2-methyl-3-phenylsulfonyl-prop-1-yl)-cyclododecanone and 0.672 g (6mmole) of potassium tert-butoxide were progressively heated to 160°under 0.02 Torr and the formed title compound directly distilled fromthe reaction mixture. There were thus isolated 0.216 g (50% yield) ofthe desired compound.

EXAMPLE 8 Bicyclo[10.3.0]pentadeca-1,12-diene

10 g (0.029 mole) of 2-(3-n-butylsulfonyl-prop-1-yl)-cyclododecanone in40 ml of toluene were heated to reflux for 30 min. in the presence ofpowdered KOH, in accordance with the process of Example 1, letter (b).After addition of 6 ml of DMSO, heating to reflux for 12 further hoursand usual treatments of extraction and distillation as previouslydescribed, the desired title compound was isolated in a 84% yield.

2-(3-n-Butylsulfonyl-prop-1-yl)-cyclododecanone used hereinabove asstarting material was prepared from 2-allyl-cyclododecanone andn-butylthiol by heating it at 95° for 10 hours in the presence ofα,α'-azoisobutyronitrile and subsequently of oxidizing and purifying itin accordance with the method given in Example 2.

Yield 88%; m.p. 91.5°.

IR: 2950, 1700, 1470, 1300, 1140 cm⁻¹ ;

NMR: 0.85-2.10 (29H, m); 2.25-3.15 (7H, m)δ ppm;

MS: M⁺ =344 (5); m/e=261 (4), 233 (9), 220 (20), 123 (48), 98 (49), 83(40), 69 (60), 55 (100), 41 (83).

What I claim is:
 1. A compound of formula ##STR11## wherein symbol Rrepresents a hydrogen atom or a methyl radical.
 2. Process for preparinga compound of formula (III) as defined in claim 1, which comprisestreating with a strong base a compound of formula ##STR12## whereinsymbol R is defined in formula (III) and Q represents an alkyl or anaryl radical.